Ômicron: understand why epistasis is key to understanding variant gravity

Ômicron is the coronavirus variant that has the most mutations, which is why it has put the world on alert.

It has about 50 mutations compared to the original virus, 26 of which are unique to it.

Since it was detected on November 24 in South Africa, scientists have started a race against time to find out whether the omicron (originally known as B.1.1.529) is more contagious, more lethal, or able to “dribble” the effect. of vaccines.

What complicates this task, however, is not the number of mutations, nor the characteristics of each one of them.

“If a variant has more mutations, it doesn’t mean that it is more dangerous, more transmissible or that it has a greater capacity to evade the effect of vaccines”, says Ed Feil, professor of microbial evolution at the University of Bath, in England.

The key to knowing what effects the variant will have, says the expert, is to understand how its mutations interact with each other.

This process is called epistasis (not to be confused with epistaxis, the scientific term for nosebleeds).

Understanding how epistasis works and what its consequences are is a real challenge for scientists.

“Even if we understand the effect of individual mutations, that doesn’t tell us how these mutations will behave when linked together,” says Feil.

What is epistasis and why is it essential in fighting the Covid-19 pandemic?

Mutation Interaction

As a virus evolves, it can accumulate a group of mutations that, in turn, can create a variant.

To detect new variants, scientists track the genomic sequence of the virus.

In this way, they identify which parts of your genome are changing as the pathogen is transmitted.

Some variants, such as omicron, are considered by the World Health Organization (WHO) as “variants of concern” because their mutations give them the potential to be more contagious, cause more serious illnesses or reduce the effect of vaccines.

This is the case with gamma, for example, originally detected in Manaus, Brazil.

But to know if the virus really has any of these abilities, it is not enough to identify that some of its mutations are capable of producing some of these effects individually.

“The combination of mutations can have effects that cannot necessarily be predicted or explained by the effect of an individual mutation,” says Feil.

“There may be a mutation that causes one effect and another mutation that causes another, but together they can have a completely different effect.”

An example of this is mentioned by evolutionary biologist Jesse Bloom in a recent article in The New York Times.

The alpha variant has a mutation called N501Y, which is associated with an increased capacity for infection.

The delta variant does not have this mutation and, however, it is more contagious than the alpha as it has other mutations that enhance its transmissibility.

For cases like this, Feil says that “the effect of an individual mutation depends on what other mutations are in the virus’s genome.”

Hard to foresee

Likewise, mutations have no additive effect.

For example, if a variant has a mutation that increases its transmission capacity by 10% and has another mutation that also increases its transmission capacity by 10%, it does not automatically mean that this variant will be 20% more contagious.

Depending on how these two mutations interact, that is, depending on the type of epistasis between them, the virus can be 40% more contagious.

But it can also happen that both mutations cancel each other out, making a variant less transmissible than expected.

“Epistasis doesn’t necessarily make the situation more dangerous, it just makes it incredibly difficult to predict how the virus will behave,” explains Feil.

In the case of the coronavirus, says Feil, it could be that the virus is undergoing so many mutations that it may be reaching a point where it self-destructs.

“But that’s a very optimistic view,” says Feil skeptically.

“The effect of epistasis could cause the virus to take a new turn at any time.”

As an example, Feil mentions that much of the battle against the virus has centered on the S protein (spike or spike) with which it binds to human cells, but it is possible that some mutations in other parts of the virus are influencing its behavior.

“We still don’t know how these mutations will interact”, says the expert.

consequences of epistasis

The omicron is particularly difficult to decipher because the number of mutations it has makes its epistasis more difficult to understand.

“This opens up more evolutionary space for this,” says Feil, adding that researchers are also forced to look at combinations that haven’t been seen before.

According to the expert, the genomic sequence of the virus can send us warning signals when it detects a dangerous mutation, but that is not enough.

“The genetic sequence tells us what a mutation can do, but it doesn’t tell us what the consequences of combining mutations in the variant will be,” says Feil.

The key is to understand what these mutations can achieve by interacting with each other.

Therefore, “it will take time to know what the omicron is really capable of”, concludes the expert.